Isoxazole derivatives as FXR agonists and methods of use thereof

Abstract

The present invention provides compounds of Formula I: and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising these compounds and methods of using these compounds to treat or prevent a disease or disorder mediated by FXR. Specifically, the present invention relates to isoxazole derivatives useful as agonists for FXR and methods for their preparation and use.

What is claimed: 
     
       1. A compound represented by Formula I or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted —C 3 -C 8  cycloalkyl; 
 R 2  is hydrogen, halogen, cyano, optionally substituted —C 1 -C 6  alkyl, optionally substituted —C 2 -C 6  alkenyl, optionally substituted —C 2 -C 6  alkynyl, optionally substituted —C 3 -C 6  cycloalkyl or optionally substituted 3- to 6-membered heterocycloalkyl; 
 A is optionally substituted aryl or optionally substituted heteroaryl; 
 R 3  is 
 
       
         
           
           
               
               
           
         
         R 4  and R 5  are independently selected from the group consisting of:
 1) Hydrogen; 
 2) Optionally substituted —C 1 -C 8  alkyl; 
 3) Optionally substituted —C 2 -C 8  alkenyl; 
 4) Optionally substituted —C 2 -C 8  alkynyl; and 
 5) Optionally substituted —C 3 -C 8  cycloalkyl; 
 
         R 7  is selected from the group consisting of:
 1) Optionally substituted —C 1 -C 8  alkyl; 
 2) Optionally substituted —C 2 -C 8  alkenyl; 
 3) Optionally substituted —C 2 -C 8  alkynyl; 
 4) Optionally substituted —C 3 -C 8  cycloalkyl; 
 5) Optionally substituted —C 3 -C 8  cycloalkenyl; 
 6) Optionally substituted aryl; 
 7) Optionally substituted arylalkyl; 
 8) Optionally substituted 3- to 8-membered heterocycloalkyl; 
 9) Optionally substituted heteroaryl; 
 10) Optionally substituted heteroarylalkyl; and 
 11) NR 8 R 9 ; wherein R 5  and R 9  are each independently selected from hydrogen, optionally substituted —C 1 -C 8  alkyl, optionally substituted —C 2 -C 8  alkenyl, optionally substituted —C 2 -C 8  alkynyl, optionally substituted —C 3 -C 8  cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, alternatively, R 8  and R 9  are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic ring. 
 
       
     
     
       2. The compound of  claim 1 , represented by Formula (II), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein R 1 , A, and R 3  are as defined in  claim 1 . 
     
     
       3. The compound of  claim 1 , represented by Formula (III), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein A and R 3  are as defined in  claim 1 . 
     
     
       4. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       5. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       6. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       7. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein -A-R 3  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein X 1  and X 2  are each independently selected from N and CH; R 6  is selected from the group consisting of halogen, OH, OCH 3 , OCH 2 F, OCF 3 , CH 3 , CH 2 F, CHF 2 , CF 3 , C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, cyano, SCF 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ; X 3  is O or S; R is hydrogen or optionally substituted —C 1 -C 6  alkyl and m is 0, 1, or 2. 
     
     
       8. The compound of  claim 1 , selected from the compounds set forth below, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       9. A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       10. A method for treating an FXR-mediated disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to  claim 1 . 
     
     
       11. The method according to  claim 10 , wherein the FXR-mediated disease or condition is selected from the group consisting of chronic liver disease, gastrointestinal disease, renal disease, cardiovascular disease, and metabolic disease. 
     
     
       12. The method according to  claim 11 , wherein the chronic liver disease is selected from the group consisting of primary biliary cirrhosis, cerebrotendinous xanthomatosis, primary sclerosing cholangitis, drug induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition associated cholestasis, bacterial overgrowth or sepsis associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, liver transplant associated graft versus host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, Sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and alpha 1-antitrypsin deficiency. 
     
     
       13. The method according to  claim 11 , wherein the renal disease is selected from the group consisting of diabetic nephropathy, focal segmental glomerulosclerosis, hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, and polycystic kidney disease. 
     
     
       14. The method according to  claim 11 , wherein the cardiovascular disease is selected from the group consisting of atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesterolemia, and hypertriglyceridemia. 
     
     
       15. The method according to  claim 11 , wherein the metabolic disease is selected from the group consisting of insulin resistance, Type I and Type II diabetes, and obesity. 
     
     
       16. The method of  claim 12 , wherein the chronic liver disease is primary biliary cirrhosis. 
     
     
       17. The method of  claim 12 , wherein the chronic liver disease is nonalcoholic fatty liver disease. 
     
     
       18. The method of  claim 12 , wherein the chronic liver disease is nonalcoholic steatohepatitis.